Global targeting of functional tyrosines using sulfur-triazole exchange chemistry
Global targeting of functional tyrosines using sulfur-triazole exchange chemistry
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DOI：
10.1038/s41589-019-0404-5
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发表时间：
2020-02-01
影响因子：
14.8
通讯作者：
Hsu, Ku-Lung
中科院分区：
文献类型：
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作者：
Hahm, Heung Sik;Toroitich, Emmanuel K.;Hsu, Ku-Lung
硫三唑交换(SuTEx)化学是选择性靶向酪氨酸的共价化学蛋白质组探针的可调平台，用于识别亲核性增强的残基和监测磷酸酪氨酸位点的激活。共价探针是全球研究蛋白质功能和配体结合能力的有价值的工具。尽管努力扩大可用于化学蛋白质组学(例如半胱氨酸和赖氨酸)的残基的覆盖范围，但目前基于活性的探针仍然无法获得很大一部分蛋白质组。在这里，我们介绍了硫三唑交换(SuTEx)化学作为一个可调的平台来开发具有广泛应用于化学蛋白质组学的共价探针。我们发现，对三氮唑离开基团的修饰可以使磺酰探针对酪氨酸的化学选择性比其他亲核氨基酸提高约5倍，以研究裂解产物和活细胞中的10,000多个酪氨酸位点。我们发现，亲核性增强的酪氨酸在酶、蛋白质相互作用和核苷酸识别结构域中都有丰富的表达。我们应用SuTEx作为一种化学磷酸蛋白质组学策略来监控磷酸酪氨酸位点的激活。总而言之，我们将SuTEx描述为用于人类蛋白质组化学生物学研究的生物相容性化学。
Sulfur-triazole exchange (SuTEx) chemistry is a tunable platform for covalent chemoproteomic probes that selectively target tyrosines, used to identify residues with enhanced nucleophilicity and monitor activation of phosphotyrosine sites.Covalent probes serve as valuable tools for global investigation of protein function and ligand binding capacity. Despite efforts to expand coverage of residues available for chemical proteomics (e.g., cysteine and lysine), a large fraction of the proteome remains inaccessible with current activity-based probes. Here, we introduce sulfur-triazole exchange (SuTEx) chemistry as a tunable platform for developing covalent probes with broad applications for chemical proteomics. We show modifications to the triazole leaving group can furnish sulfonyl probes with ~5-fold enhanced chemoselectivity for tyrosines over other nucleophilic amino acids to investigate more than 10,000 tyrosine sites in lysates and live cells. We discover that tyrosines with enhanced nucleophilicity are enriched in enzymatic, protein-protein interaction and nucleotide recognition domains. We apply SuTEx as a chemical phosphoproteomics strategy to monitor activation of phosphotyrosine sites. Collectively, we describe SuTEx as a biocompatible chemistry for chemical biology investigations of the human proteome.